Association of assisted reproductive technology (ART) treatment and parental infertility diagnosis with autism in ART-conceived children.

STUDY QUESTION: Are assisted reproductive technology (ART) treatment factors or infertility diagnoses associated with autism among ART-conceived children? SUMMARY ANSWER: Our study suggests that the incidence of autism diagnosis in ART-conceived children during the first 5 years of life was higher when intracytoplasmic sperm injection (ICSI) was used compared with conventional IVF, and lower when parents had unexplained infertility (among singletons) or tubal factor infertility (among multiples) compared with other types of infertility. WHAT IS KNOWN ALREADY: Some studies found an increased risk of autism among ART-conceived infants compared with spontaneously-conceived infants. However, few studies, and none in the USA, have examined the associations between types of ART procedures and parental infertility diagnoses with autism among ART-conceived children. STUDY DESIGN, SIZE, DURATION: Population-based retrospective cohort study using linkages between National ART Surveillance System (NASS) data for 1996-2006, California Birth Certificate data for 1997-2006, and California Department of Developmental Services (DDS) Autism Caseload data for 1997-2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: All live born ART-conceived infants born in California in 1997-2006 (n = 42 383) with 5-year observation period were included in the study. We assessed the annual incidence of autism diagnosis documented in DDS, which includes information on the vast majority of persons with autism in California, and the association of autism diagnosis with ART treatment factors and infertility diagnoses. MAIN RESULTS AND THE ROLE OF CHANCE: Among ART-conceived singletons born in California between 1997 and 2006, the incidence of autism diagnosis remained at ∼0.8% (P for trend 0.19) and was lower with parental diagnosis of unexplained infertility (adjusted hazard risk ratio [aHRR]; 95% confidence interval: 0.38; 0.15-0.94) and higher when ICSI was used (aHRR 1.65; 1.08-2.52), when compared with cases without these patient and treatment characteristics. Among ART-conceived multiples, the incidence of autism diagnosis between 1997 and 2006 remained at ∼1.2% (P for trend 0.93) and was lower with parental diagnosis of tubal factor infertility (aHRR 0.56; 0.35-0.90) and higher when ICSI was used (aHRR 1.71; 1.10-2.66). LIMITATIONS, REASONS FOR CAUTION: Study limitations include imperfect data linkages, lack of data on embryo quality and possible underestimation of autism diagnosis cases. Limitations of the observational study design could affect the analysis by the possibility of residual confounders. Since information about ICSI use was missing for most frozen/thawed embryo transfer cycles, our findings of association of ICSI use and autism diagnosis can only be generalizable to fresh embryo transfer cycles. WIDER IMPLICATIONS OF THE FINDINGS: Our study provides additional evidence of the association between some types of ART procedures with autism diagnosis. Additional research is required to explain the increased risk of autism diagnosis with ICSI use, as well as studies on the effectiveness and safety of ICSI.

The prohibitin family of mitochondrial proteins regulate replicative lifespan.

Cellular senescence is determined by multiple factors, including the genetic regulation of metabolism and responses to endogenous and exogenous stresses [1-4]. Recent studies implicate a limited number of gene products in elongating lifespan in yeast and Caenorhabditis elegans [2-4]; these include the C, elegans gene cik-1, a central regulator of metabolism [5], and yeast RAS2, which controls the response to ultraviolet irradiation and other stresses [3]. Another gene postulated to effect senescence is PHB1, the yeast homologue of prohibitin [3], a rodent gene initially identified as a potential regulator of growth arrest and tumour suppressor [6-8]. Highly conserved prohibitin homologues have been identified in mammals [9], Drosophila [10], C. elegans [9], plants [11] and yeast. A second mammalian gene, encoding BAP37, a protein with sequence similarity to prohibitin, is thought to be involved in lymphocyte function [9]. Here, we show that the nuclear-encoded mammalian prohibitin and BAP37 proteins are present in mitochondria, are co-expressed, and interact physically with each other. Deletion of the Saccharomyces cerevisiae homologues, PHB1 and PHB2, results in a decreased replicative lifespan and a defect in mitochondrial membrane potential. Our observations highlight the relationship between the metabolic efficiency of cells and the ageing process, and provide evidence for its evolutionary conservation.

p68 RNA helicase: identification of a nucleolar form and cloning of related genes containing a conserved intron in yeasts.

The human p68 protein is an RNA-dependent ATPase and RNA helicase which was first identified because of its immunological cross-reaction with a viral RNA helicase, simian virus 40 large T antigen. It belongs to a recently discovered family of proteins (DEAD box proteins) that share extensive regions of amino acid sequence homology, are ubiquitous in living organisms, and are involved in many aspects of RNA metabolism, including splicing, translation, and ribosome assembly. We have shown by immunofluorescent microscopy that mammalian p68, which is excluded from the nucleoli during interphase, translocates to prenucleolar bodies during telophase. We have cloned 55% identical genes from both Schizosaccharomyces pombe and Saccharomyces cerevisiae and shown that they are essential in both yeasts. The human and yeast genes contain a large intron whose position has been precisely conserved. In S. cerevisiae, the intron is unusual both because of its size and because of its location near the 3' end of the gene. We discuss possible functional roles for such an unusual intron in an RNA helicase gene.

HIV-1 seroprevalence rates in women and relinquishment of infants to the state in St Petersburg, Russia, 2002.

The effectiveness of rapid HIV-1 testing and nevirapine prophylaxis for HIV-infected mothers without prenatal care has been shown. We found that from 1998 to 2002, HIV-1 seroprevalence in women giving birth in St Petersburg, Russia increased 100-fold: from 0.013% to 1.3% (p<0.0001). HIV-1 seroprevalence was 8% (114 of 1466) in women without prenatal care and 1% (376 of 37645) in those with prenatal care (p<0.0001). All 376 HIV-1-infected women with, and 41% (47 of 114) of HIV-1-infected women without prenatal care received intrapartum antiretroviral therapy (p<0.0001). In women who were HIV-1 positive, 26% (30 of 114) of those without prenatal care and 4% (13 of 371) of those with prenatal care relinquished their infants to the custody of the state, compared with 1% (354 of 37 621) of HIV-1-negative women (p<0.0001).

Molecular characterization of the oligopeptide permease of Salmonella typhimurium.

The oligopeptide permease (Opp) of Salmonella typhimurium is a periplasmic binding protein-dependent transport system and handles any peptides containing from two to five amino acid residues. Opp plays an important nutritional role and is also required for the recycling of cell wall peptides. We have determined the nucleotide sequence of the opp operon. In addition to the four opp genes identified previously by genetic means (oppABCD) a fifth gene, oppF, is shown to be cotranscribed as part of the opp operon. Using reverse genetics, we show that oppF also encodes an essential component of the Opp transport system. The five proteins, OppABCDF, are shown to be the only proteins required for Opp function. Regulation of opp expression and of the differential expression of genes within the operon is investigated. We have devised a simple means of constructing lacZ gene fusions to any S. typhimurium chromosomal gene in vivo, using derivatives of bacteriophage Mu. Using this procedure, opp-lacZ gene fusions were selected. The resultant Opp-LacZ hybrid proteins were used to show that OppB, OppC and OppD are membrane-associated proteins. A detailed comparison of the Opp components with those of other binding protein-dependent transport systems provides insight into the mechanisms and evolution of these transport systems.

HIV-1 subtype E progression among northern Thai couples: traditional and non-traditional predictors of survival.

BACKGROUND: In the continuing effort to introduce antiretroviral therapy in resource-limited settings, there is a need to understand differences between natural history of HIV in different populations and to identify feasible clinical measures predictive of survival. METHODS: We examined predictors of survival among 836 heterosexuals who were infected with HIV subtype CRF01_AE in Thailand. RESULTS: From 1993 to 1999, 269 (49.4%) men and 65 (25.7%) women died. The median time from the estimated seroconversion to death was 7.8 years (95% confidence interval 7.0-9.1). Men and women with enrolment CD4 counts <200 cells/microl had about 2 and 11 times greater risk of death than those with CD4 counts of 200-500 and >500, respectively. Measurements available in resource-limited settings, including total lymphocyte count (TLC), anaemia, and low body mass index (BMI), also predicted survival. Men with two or more of these predictors had a median survival of 0.8 (0.5-1.8) years, compared with 2.7 (1.9-3.3) years for one predictor and 4.9 (4.1-5.2) years for no predictors. CONCLUSIONS: The time from HIV infection to death appears shorter among this Thai population than among antiretroviral naive Western populations. CD4 count and viral load (VL) were strong, independent predictors of survival. When CD4 count and VL are unavailable, individuals at high risk for shortened HIV survival may be identified by a combination of low TLC, anaemia, and low BMI. This combination of accessible clinical measures of the disease stage may be useful for medical management in resource-limited settings.

The prevalence of dysmenorrhea, dyspareunia, pelvic pain, and irritable bowel syndrome in primary care practices.

OBJECTIVE: To determine the prevalence of dysmenorrhea, dyspareunia, pelvic pain, and irritable bowel syndrome in a clinical population of reproductive-age women. METHODS: A ten-page questionnaire was administered to a consecutive sample of women age 18-45 years who were approached in the waiting areas of two obstetrics and gynecology practices and three family medicine practices in central North Carolina. Of 701 women approached to fill out the questionnaire, 581 (83%) returned completed forms suitable for analysis. RESULTS: The reported prevalence of dysmenorrhea, dyspareunia, pelvic pain, and irritable bowel syndrome was 90, 46, 39, and 12%, respectively. Low income was found to be a risk factor for dysmenorrhea and dyspareunia, and African-American race was found to be a risk factor for pelvic pain. Pelvic pain was also more common among women 26-30 years old. Otherwise, dysmenorrhea, dyspareunia, pelvic pain, and irritable bowel syndrome were not associated with age, parity, marital status, race, income, or education. CONCLUSION: Dysmenorrhea, dyspareunia, pelvic pain, and irritable bowel syndrome are common complaints among women of reproductive age and are not consistently associated with demographic risk factors. Therefore, inquiry about these pelvic pain complaints should be a routine part of health care for women.

Complications of interval laparoscopic tubal sterilization: findings from the United States Collaborative Review of Sterilization.

OBJECTIVE: To estimate the risk of intraoperative or postoperative complications for interval laparoscopic tubal sterilizations. METHODS: We used a prospective, multicenter cohort study of 9475 women who had interval laparoscopic tubal sterilization to calculate the rates of intraoperative or postoperative complications. The relative safety of various methods was assessed by calculating overall complication rates for each major method of tubal occlusion. Method-related complication rates also were calculated and included only complications attributable to a method of occlusion. We used logistic regression to identify independent predictors of one or more complications. RESULTS: When we used a more restrictive definition of unintended major surgery, the overall rate of complications went from 1.6 to 0.9 per 100 procedures. There was one life-threatening event and there were no deaths. Complications rates for each of the four major methods of tubal occlusion ranged from 1.17 to 1.95, with no significant differences between them. When complication rates were calculated, the spring clip method had the lowest method-related complication rate (0.47 per 100 procedures), although it was not significantly different from the others. In adjusted analysis, diabetes mellitus (adjusted odds ratio [OR] 4.5; 95% confidence interval [CI] 2.3, 8.8), general anesthesia (OR 3.2; CI 1.6, 6.6), previous abdominal or pelvic surgery (OR 2.0; CI 1.4, 2.9), and obesity (OR 1.7; CI 1.2, 2.6) were independent predictors of one or more complications. CONCLUSION: Interval laparoscopic sterilization generally is a safe procedure; serious morbidity is rare.

Longitudinal analysis of bacterial vaginosis: findings from the HIV epidemiology research study.

OBJECTIVE: To determine the natural history of bacterial vaginosis in women with or at risk for human immunodeficiency virus (HIV). METHODS: A cohort of 854 HIV-infected women and 434 HIV-uninfected women from four US sites was followed prospectively with gynecologic exams every 6 months over a 5-year period. The prevalence, incidence, persistence, and severity of bacterial vaginosis, which was defined using a Gram-staining scoring system, were calculated using generalized estimating equation methods. RESULTS: In adjusted analyses, HIV-infected women had a higher prevalence of bacterial vaginosis than HIV-uninfected women (adjusted odds ratio [OR] 1.29; 95% confidence interval [CI] 1.08, 1.55). Although HIV-infected women were not more likely to have incident infections, they were more likely to have persistence of their infections (adjusted OR 1.49; 95% CI 1.18, 1.89). Similarly, immunocompromised women (CD4+ cell count less than 200 cells/microL) were more likely than HIV-infected women with higher CD4+ cell counts (more than 500 cells/microL) to have prevalent (adjusted OR 1.29; 95% CI 1.03, 1.60) and persistent (adjusted OR 1.38; 95% CI 1.01, 1.91) bacterial vaginosis infections, but not more likely to have incident infections. Immunocompromised women had more severe bacterial vaginosis by both clinical criteria (adjusted OR 1.40; 95% CI 1.08, 1.82) and by Gram-staining criteria (adjusted OR 1.50; 95% CI 1.12, 2.00). CONCLUSIONS: Bacterial vaginosis is more prevalent and persistent among HIV-infected women, particularly among those who are immunocompromised. Immunocompromised women are more likely than HIV-infected women with higher CD4+ cell counts to have severe bacterial vaginosis.

Glutathione is an important antioxidant molecule in the yeast Saccharomyces cerevisiae.

The tripeptide gamma-L-glutamyl-L-cystinylglycine (glutathione) is one of the major antioxidant molecules of cells and is thought to play a vital role in buffering the cell against reactive oxygen species and toxic electrophiles. We wished to determine the role of glutathione in the protection of the yeast Saccharomyces cerevisiae against oxidative stress. This study shows that glutathione is an important antioxidant molecule in yeast, with gamma-glutamylcysteine synthetase (gsh1) mutants, deficient in glutathione synthesis, being hypersensitive to H2O2 and superoxide anions in both exponential- and stationary-phase cultures. Despite this, these mutants are still able to induce adaptive stress responses to oxidants.

Analysis of the adaptive oxidative stress response of Candida albicans.

Treatment of Candida albicans with low concentrations of either hydrogen peroxide or menadione (a superoxide generating agent) induces an adaptive response which protects cells from the lethal effects of a subsequent challenge with higher concentrations of these oxidants. Pre-treatment with either menadione or hydrogen peroxide is protective against cell killing by either oxidant. This suggests that the pathogenic yeast C. albicans (unlike the budding yeast Saccharomyces cerevisiae which has separate responses) possesses an adaptive response that responds to both these oxidants. In addition, we found that C. albicans showed a greater level of resistance to oxidants, both H2O2 and redox-cycling agents, compared to that observed with S. cerevisiae. In an attempt to characterise the oxidative stress response in more detail we have analysed the effect of oxidants on the activities of a number of enzymes with known antioxidant activity.

The effect of oxidative stress on Saccharomyces cerevisiae.

Reactive oxygen species (ROS) are highly reactive and damage cellular constituents such as DNA, lipids and proteins. All aerobically growing organisms are exposed to ROS. As a result most organisms have evolved mechanisms to protect their components against ROS. This review describes the oxidant defence systems of the yeast Saccharomyces cerevisiae, which is an ideal eukaryotic model system to analyse the molecular events in response to oxidative stress. Yeast posses a similar range of anti-oxidant molecules and enzymes to those found in higher eukaryotes. Exponentially growing S. cerevisiae have at least two distinct adaptive stress responses to oxidants, one of which is responsive towards H2O2 and the other is induced by exposure to compounds that generate superoxide anion. The identification of a number of transcription factors (Yap1, Mac1, Ace1) which are important in the regulation of metal metabolism and homeostasis that are also involved in mediating resistance towards oxidants suggests a link between metal metabolism and oxidative stress. Heat-shock, nutrient starvation and entry into the stationary phase of growth also lead to increased resistance toward oxidants. The available evidence suggests that the mechanism by which these stresses result in oxidant resistance may be different from those utilised by exponentially growing cells.

Pregnancy outcomes in foreign-born and US-born women.

OBJECTIVES: To compare pregnancy outcomes between foreign-born women and women born in the United States (US-born). METHODS: A retrospective cohort study (1991-2001) of all deliveries at Grady Memorial Hospital in Atlanta, Georgia. RESULTS: Among 49,904 deliveries, 27% were to foreign-born mothers representing 164 countries grouped into eight geographic regions. Compared with US-born women, foreign-born women had a higher mean birthweight (3315 vs. 3083 g), and a lower risk of preterm delivery (RR 0.46, 95% CI 0.43-0.49), perinatal mortality (RR 0.40, 95% CI 0.36-0.45), hypertension (RR 0.31, 95% CI 0.23-0.41), and HIV infection (RR 0.13, 95% CI 0.10-0.18). However, foreign-born women had an increased risk of diabetes (RR 1.63, 95% CI 1.48-1.79), perineal laceration (RR 1.71; 95% CI 1.66-1.76), and postpartum hemorrhage (RR 1.10; 95% CI 1.05-1.15). CONCLUSIONS: Foreign-born women have better health behaviors, pregnancy outcomes, and a lower risk of infectious diseases than US-born women, but they have a higher risk of certain medical conditions and obstetric complications.

Multicity HIV seroprevalence in street youth, Ukraine.

We conducted the first systematic, community-based, multicity assessment outside the USA of HIV seroprevalence, risk factors and linkage into clinical services among 929 street youth. After city-wide mapping, we used time-location sampling and randomly selected 74 venues in Odesa, Kyiv and Donetsk, Ukraine. Rapid HIV testing with post-test counselling was offered to all eligible youths aged 15-24 years. Overall, 18.4% (95% confidence interval 16.2-20.2) were HIV positive and 85% had previously unknown status. Rates were identical by sex. Subgroups with highest rates included orphans (26%), youths with histories of exchanging sex (35%), sexually transmitted infections (STIs) (37%), injection drug use (IDU) (42%) and needle sharing (49%). Independent predictors, similar across age groups and city, included being orphaned, time on the street, history of anal sex, STIs, exchanging sex, any drug use, IDU and needle sharing. Two-thirds (68%) of HIV-positive youths were linked to services. This high-risk population has many immediate needs.

Saccharomyces cerevisiae has distinct adaptive responses to both hydrogen peroxide and menadione.

Treatment of Saccharomyces cerevisiae cells with low concentrations of either hydrogen peroxide or menadione (a superoxide-generating agent) induces adaptive responses which protect cells from the lethal effects of subsequent challenge with higher concentrations of these oxidants. Pretreatment with menadione is protective against cell killing by hydrogen peroxide; however, pretreatment with hydrogen peroxide is unable to protect cells from subsequent challenge with menadione. This suggests that the adaptive responses to these two different oxidants may be distinct.

Oxidative stress responses of the yeast Saccharomyces cerevisiae.

All aerobically growing organisms suffer exposure to oxidative stress, caused by partially reduced forms of molecular oxygen, known as reactive oxygen species (ROS). These are highly reactive and capable of damaging cellular constituents such as DNA, lipids and proteins. Consequently, cells from many different organisms have evolved mechanisms to protect their components against ROS. This review concentrates on the oxidant defence systems of the budding yeast Saccharomyces cerevisiae, which appears to have a number of inducible adaptive stress responses to oxidants, such as H2O2, superoxide anion and lipid peroxidation products. The oxidative stress responses appear to be regulated, at least in part, at the level of transcription and there is considerable overlap between them and many diverse stress responses, allowing the yeast cell to integrate its response towards environmental stress.

A suppressor of yeast spp81/ded1 mutations encodes a very similar putative ATP-dependent RNA helicase.

The spp81/ded1 mutations were isolated as suppressors of a Saccharomyces cerevisiae pre-mRNA splicing mutation, prp8-1. The SPP81/DED1 gene encodes a putative ATP-dependent RNA helicase. While attempting to clone the wild-type SPP81/DED1 gene we isolated plasmids which were able to suppress the cold-sensitive growth defect of spp81 mutants. These plasmids encoded a gene (named DBP1) which mapped to chromosome XVI and not to the SPP81/DED1 locus on chromosome XV. The cloned gene suppressed the defect of spp81/ded1 mutants when present on both high and low copy-number plasmids but complemented spp81/ded1 null mutants only when present on high copy-number plasmids. In contrast to the SPP81/DED1 gene the DBP1 gene was not essential for cell viability. The nucleotide sequence of the DBP1 gene revealed that it also encoded a putative ATP-dependent RNA helicase which showed considerable similarity at the amino acid level to the SPP81/DED1 protein.

Two genetically distinct pathways for transcriptional regulation of anaerobic gene expression in Salmonella typhimurium.

Expression of the tripeptide permease gene tppB is anaerobically induced. This induction is independent of the fnr (oxrA) gene product, which is known to be required for the anaerobic induction of several respiratory enzymes. We isolated, characterized, and mapped mutations in two genes, oxrC and tppR, which prevent the anaerobic induction of tppB expression. Mutations in oxrC were highly pleiotropic, preventing the anaerobic expression of the formate dehydrogenase component of formate hydrogen lyase (fhl), a tripeptidase (pepT), and two of the three known hydrogenase isoenzymes (hydrogenases 1 and 3). On the other hand, expression of nitrate reductase, fumarate reductase, and a number of other fnr (oxrA)-dependent enzymes was not affected by mutations in oxrC. Thus, there appeared to be at least two distinct classes of anaerobically induced genes, those which required fnr for their expression and those which required oxrC. It seems that fnr-dependent enzymes perform primarily respiratory functions, whereas oxrC-dependent enzymes served fermentative or biosynthetic roles. We found the primary defect of oxrC mutants to be a deficiency in phosphoglucose isomerase activity, implying that a product of glycolysis functions as an anaerobic regulatory signal. Mutations in tppR were specific for tppB and did not affect expression of other oxrC-dependent genes. However, tppR did exhibit phenotypes other than the regulation of tppB. Both oxrC and tppR mutants were hypersensitive to the toxic NAD analog 6-aminonicotinic acid. This suggests that oxrC and tppR may play a role in the regulation of NAD biosynthesis or, alternatively, that NAD or a related nucleotide serves as the anaerobic signal for oxrC-dependent enzymes.

The effect of family planning participation on prenatal care use and low birth weight.

Data on approximately 45,000 North Carolina women who gave birth in 1989 and 1990 and received prenatal care in public health facilities were studied to assess the effects in a low-income population of prior family planning services on low birth weight and adequacy of prenatal care. Women who had used family planning services in the two years before conception were significantly more likely than those who had not used such services to have a birth-to-conception interval of greater than six months. They were also more likely to receive early and adequate prenatal care and to be involved in a food supplement program and maternity care coordination. In addition, the family planning participants were less likely than the nonparticipants to be younger than 18 and were somewhat less likely to deliver a low-birth-weight infant. Though the results of this retrospective study must be interpreted with caution because of such factors as self-selection into family planning programs, they suggest that family planning services may improve birth weight and use of prenatal health services among low-income women.

PIP: To determine the effects of prior use of family planning services on birth weight and adequacy of prenatal care, researchers compared data on 14,338 low-income women who gave birth in North Carolina during 1989-1990 and had earlier attended family planning services at public health clinics with data on 30,761 low-income women who also gave birth in 1989-1990 but did not use family planning services. Both groups of women basically matched in terms of education, Medicaid coverage, marital status, smoking history, medical risk factors, and previous incompleted pregnancy, or infant or child mortality. Most women who used family planning services were black (64% vs. 48.1%). 18-year old and younger women who used family planning services had fewer births than those who did not use family planning services (7.2% vs. 14.7% for whites and 9.6% vs. 19.7% for blacks; p .001). Further, women who used family planning services were more likely to participate in the food supplementation program referred to as WIC (89.9% vs. 86.6% for blacks and 87.9% vs. 81.7% for whites; p .001) and in the maternity care coordination program for Medicaid recipients (59.4% vs. 52.9% for blacks and 50.2% vs. 44.1% for whites; p .001). Moreover, they tended to receive earlier and more adequate prenatal care (51.6% receiving no are in 1st trimester vs. 58.3% receiving care in 1st trimester for blacks, and 40% vs. 47.1% for whites, and 51.6% vs. 58.3% for blacks and 40% vs. 47.1% for whites; p .001 respectively). They were also less likely to deliver a low birth weight (LBW) infant than those who did not use these services, but the difference was only significant for blacks (13.1% for no visits vs. 12.2% for any visit [p .05] and 11.6% for at least 3 visits [p .1]); for whites, 7.9% for no visits vs. 7.4% for any visit and at least 3 visits. Despite the possibility of self selection bias, these findings indicate that family planning services reduce the incidence of LBW and improve use of prenatal health services.